2-Amino-2-deoxy-D-mannose (D-mannosamine) mainly in its N-acetylated form (ManNAc) can be found as a building unit of some bacterial capsular polysaccharides and lipopolysaccharides. In addition, N-acetyl-D-mannosamine is the biosynthetic precursor of sialic acid, a unique nine-carbon ketoaldonic acid having many major biological roles.
One can obtain D-mannosamine or N-acetyl-D-mannosamine by means of chemical or enzymatic transformations. N-Acetyl-D-glucosamine can be converted into N-acetyl-D-mannosamine via 2-epimerization which can be initiated with bases (organic or inorganic bases as well as basic ion exchange resins are suitable) or epimerase enzymes [1-3]. In these methodologies an equilibrium between N-acetyl-D-glucosamine and N-acetyl-D-mannosamine is formed wherein the gluco compound is favoured, thus sophisticated and/or complicated separation techniques are needed to isolate this minor product from the starting material remaining, reagent and/or enzymes and other undesired by-products. The isolation difficulties, the moderate chemical yield and the relative expense of the starting compound all prevent this procedure being scaled-up in a cost-effective way. In classical synthetic methods, cheap and easily available simple monosaccharides can be transformed into the D-mannosamine framework like D-arabinose (stereoselective aminohomologation of D-arabinose chain via thiazole addition to nitrone [4,5], addition of ammonia to D-arabo-tetraacetoxy-1-nitro-1-hexene [6]), D-glucose (nucleophilic displacement of good leaving groups in C-2 with N-nucleophiles [7], stereoselective reduction of 2-gluculose oximes [8,9]) or D-glucal (intermolecular addition of nitrosyl chloride to the double bond [10], azidonitration of the double bond [11], intramolecular rhodium(II)-catalyzed oxidative cyclization of glucal-3-carbamates [12,13], [3,3]sigmatropic rearrangement of 4-O-trichloroacetimidyl-hex-2-enopyranosides derived from glucal [14]). These chemical pathways always stand in need of extensive use of protecting groups in order to mask functional groups that would be affected by the key transformational step(s), thus they consist of many elementary chemical steps. Such multistep sequences restrict usefulness and are not attractive for large scale developments because of the long technological time and the use of high number of reagents (which in fact, not uncommonly, can be toxic, of low availability and/or expensive) and/or require lengthy or cumbersome isolation/separation procedures.
Reaction of a ketose with an amine giving a ketosyl amine and the subsequent rearrangement of the latter into 2-amino-2-deoxy-aldose is known as Heyns-rearrangement [15]. Theoretically both 2-epimers can be formed, nevertheless the formation of one of the epimers is favoured, presumably because of steric factors. In the Heyns-rearrangement of D-fructose with a primary amine the exclusive formation of the corresponding gluco derivative is observed. Particularly, crystalline fructosyl benzyl amine, obtained as an intermediate by reacting D-fructose with benzyl amine, rearranges exclusively to 2-benzylamino-2-deoxy-D-glucose upon treatment with glacial acetic acid in methanol [16]. On the other hand, the formation of N-benzyl-2-benzylamino-2-deoxy-D-glucopyranosylamine was reported in the reaction of D-fructose with benzyl amine (the latter serves as reactant and solvent also) upon heating [17] or in the presence of a catalytic amount of benzyl ammonium chloride or ZnCl2[18,19].
The synthesis of N-alkyl- or N-(substituted alkyl)-mannosamine glycosides is possible in a tandem reduction-reductive alkylation reaction of 2-azido-2-deoxy-mannose derivatives in the presence of an alkanal or substituted alkanal [20].
The biological significance of mannosamine derivatives always provides an incentive for developing new, short and simple synthetic routes towards them that can be easily scaled-up. It is an aim of the present invention to provide such a method.